single genes. The mGluRs do not form ion channels but are instead linked to signal transduction molecules within the plasma membrane. mGluRs have slower electrophysiological characteristics (latencies > 100 msec) than ion channel GluRs. Group I mGluRs (mGluR1 and mGluR5) operate through activation of phospholipase C (PLC) by Gq proteins, phosphoinositide hydrolysis and generation of inositol 1,4,5-triphosphate and diacylglycerol, and subsequent mobilization of Ca2+ from nonmitochondrial intracellular stores. Group II mGluRs (mGluR2 and 3) and group III mGluRs (mGluR4 and 6-8) function by GI-or Go-protein-mediated inhibition of adenylyl cyclase and modulation of ion channel activity.

Although glutamate and GluR activation are critical for normal nervous system function, glutamate is toxic to neurons at abnormally high concentrations if the GluRs on neurons are excessively activated. This process is called excitotoxicity. The excessive stimulation of GluRs by glutamate or chemical analogs of glutamate produces abnormalities in intracellular ions, pH, protein phosphorylation, energy levels, and reactive oxygen species. Acute excitotoxicity causes degeneration in neuronal cultures of animal brain and spinal cord and after intracerebral delivery of GluR activators into the CNS of experimental animals. In addition, excitotoxicity participates in the mechanisms for neuronal degeneration in animal models ofcerebral ischemia, as well as brain and spinal cord trauma, and in the neurotoxicity in humans resulting from consumption of mussels contaminated with the KA receptor activator domoic acid. Excitotoxicity is also suspected as a culprit in the nerve cell loss associated with AD, ALS, Huntington's disease, and Parkinson's disease.

The precise mechanisms for GluR-mediated excito-toxic degeneration of neurons are not understood. Both neuronal culture and animal model data are discordant with regard to whether excitotoxic neuronal death is apoptosis or necrosis. Activation of neuronal GluRs kills neurons by pathways that may involve alterations in cytosolic free Ca2+ homeostasis and activation of Ca2+-sensitive proteases, protein kinases, endonucleases, lipases, and phospholipases. Excitotoxicity results in an activation of endonucleases (DNA-cleaving enzymes) and internucleosomal digestion of genomic DNA into 180-200 base pair fragments 12-48 hr after intracerebral injections of excitotoxins in rats. Internucleosomal fragmentation of DNA also occurs in cultures of cortical neurons, although others have not found internucleosomal DNA fragmentation in cell culture.

The structural changes that occur in neurons in the adult rat brain after an excitotoxic insult include swelling and vacuolation of the cell body and dendrites, fragmentation of the nucleus into irregular clumps of chromatin, and damage to membranous organelles including the Golgi apparatus, endoplasmic reticulum, and mitochondria. This damage is thought to be typical of cellular necrosis (Fig. 9). However, in the immature brain, excitotoxicity can cause neuronal death very similar to apoptosis.

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